3, 3-dimethoxy-20-spirox-5(10)-ene-21-one and process of preparation



United States Patent 3,058,976 3,3DIMETHGXY-Z0-SPlROX-5(10)-ENE-2l-DNE AND PROCESS OF PREPARATION Arthur A. Patchett, Metuchen, N.J., assignor to Merck & (30., Inc., Railway, N.J., a corporation of New Jersey No Drawing. Filed June 27, 1960, Ser. No. 38,752 7 Claims. (Cl. 260-23957) The novel l9-nor-22-halogen spirox-4-ene-3,21- diones which form the subject of the present invention accordingly are compounds having the following structural formula:

wherein X stands for a halogen atom.

This invention also contemplates the preparation of additional compounds of the foregoing structure, having other substituents in the ring, and more particularly, the ll-oxygenated and the 7a-lower alkanoylthio derivatives, as well as the lower alkyl, cyclohexyl and benzyl 3-enol ethers thereof. Among the radicals comprehended by the expression lower alkanoyl are formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl, heptanoyl, and branched-chain isomers thereof, said alkanoyl radicals being the acyl radicals of alkanoic acids containing fewer than nine carbon atoms.

These novel steroids block the salt-retaining eifects of aldosterone and other salt-retaining steroids so as to be useful in the treatment of diseases such as congestive heart failure, nephrosis and cirrhosis of the kidney in which aldosterone secretion is increased.

In preparing my novel chemical compounds, the starting material utilized is the 3-methoxy-l7a-[2-carboxy- 2 ethyl]-2,5(10)-androstadiene-17fi-ol, which has the following formula:

0 I no CHr-OHzJi-QH (EH30 Upon treatment of 3,3-dimethoxy-20-spirox-5(10)-ene-21- one with an oxalate ester and a non-aqueous strong base such as sodium hydride, there is formed 3,3-dimethoxy-22- methoxyalyl-20-s'pirox-5(10)-ene-2l-one, which has the following structure:

OHaO

The 3,3-dimethoxy 22 fluoro-20-spiroX-5( 10 fine-2F one which has the following structure:

CHaO

CHaO

. 3 4- i p par y Contacting 3,3- imetl10Xy-22-methoxa1yl- The 22halo-l9-nor-20-spirox-4,6-diene-3,21-dione is 20-SPiY0X-5(10)-6116410118 t an alkali m al o ide to heated with a lower thioalkanoic acid to give 7u-lower alform the enolate, which on reaction with perchloryl kanoylthio 22 -halo- 19- nor-20-spirox-4-ene-3,2l-dione fluoride gives the 22a-fluoro-22-alkoxalyl derivative. The which has the following structure: latter compound is then converted into a 3-3-dimethoxy- 22-fluoro-20-spirox-5(10)-ene-211-one on treatment with an alkali metal alkoxide.

The 3,3 dimethoxy-ZZ-bromo-ZO-spirox-S ()-ene-21- 0 one, which has the following structure:

OHIO The above reaction proceeds fairly rapidly at elevated 0H3o temperatures, such as those in excess of 50 C. and can be carried out optionally under the. influence of ultraviolet light. In carrying out the additionreaction with lower boiling thioalkanoic acids, such as thioacetic acid, it is convenient to conduct the reaction at the reflux tempera- 25 ture of the reaction mixture; whereas with higher boiling b f ifi i g i gg ggg ggigggi thioalkanoic acids it is convenient to conduct the reaction at a temperature of about 90100 C. Heating periods of 0 01 up to a few hours are suflicient to achieve substantial conversion to the desired reaction products. Typically, the o desired compound is obtained in a satisfactory state of purity by direct filtration of the cooled reaction mixture, preceded, where necessary by removal of excess thioalkanoic acid. If desired, however, the reaction product can be purified by chromatography using adsorbents such as silica gel or acid-washed alumina, followed by elution with mixtures of ethyl acetate in benzene.

l wherein X stands for a halogen atom.

is obtained by treating 3,3-dimethoxy-ZZ-rnethoxyalyl-20- spirox-5'( 10) -ene-2l-one first with bromine in the presence of an organic base such as pyridine, and then with an alkali metal alkoxide.

CH O

The addition of thioalkanoic acids to the 6,7-double 3 bond of the starting materials employed in the practice of 15 -formed by treatmg 33-dnpethoxyizz'inethoxaly1'20' this invention proceeds under steric influences such as splrox'sumfene'zl'one first i m the pr?sence 40 that of the stereoisomersformed, one is obtained in preof organic such as pyndme and then wlth an dominant amount, which, in each case, has been charalkah metal.alkoxlde' v acterized' herein 'as possessing the a-configuration'of the i i F' 7 acylthio group. However, the designated configuration dissolved m a su table solvent such as acetone, is treated of the 7 acylthio group is based upon an analysis of molec with an acid catalyst, for example p-toluenesulfonic acid n1 7 a ar rotation data presently appearing in the chemical to g1 v6 22'ha1m19'n0r Whlch literature, and is therefore not to be interpreted except in hasthe followmg Structure: relation to the state of the art presently known to organic NWX chemists. It will be apparent that no part of the specification will be materially defective if it should later be es- 0 tablished that the configuration is the opposite of that deducible from data presently available'to workers in the field.

A further embodiment of our invention comprises novel pharmaceutical compositions containing these 22-halo-l9- nor-20-spirox-4-ene-3,21-diones exemplified in the foregoing structures. A preferred embodiment of our invention comprises pharmaceutical compositions containing D these 22-fluoro l9 nor-20-spirox-4-ene-3,2l-dione cornwherem X stands for a halogen atom. pounds combined with diuretics such as chlorothiazide,

Heating 22-halo-19-nor-20-spirox-4-ene-3,2l-dione with hydrochlorothiazide and related compounds. chloranil in a solvent such as t-butanol gives 22-ha1o-19- The following examplesillustrate methods of carrying nor-20-spirox-4,6-diene3,21dione which has the followout the present invention but it is to be understood that ing structure: these examples are given for purposes of illustration and not of limitation.

Example 1 100 mg. of 3-methoxy-l7a-[2-carboxyethyl]-2,5(10)- androstadiene-17/3-o1 is dissolved in 5 cc. of anhydrous methanol. To this solution isadded about 10 mg. of

anhydrous p-toluenesulfonic acid. The reaction mixture is left at room temperature for 45 minutes and then about 5 drops of pyridine is added'to destroy the acid. The methanol is then blown oil? with nitrogen and the residue taken up in ether and washed with bicarbonate wherein X stands for a halogen atom. solution and water. Chromatography over alumina af- ZZZZU Example 2 Dimethyl oxalate (3.5 gms.) is dissolved in 30 cc. of benzene. The solution is then azeotropically dried to a volume of 25 cc. Sodium hydride (1.050 g), as a 52.7% dispersion in oil, is added. A slight reaction occurs. To this grey suspension is added 687 mg. of 3,3- dimethoxy-ZO-spirox-S 10) -ene-21-one. The reaction mixture is held at 40 C. overnight with magnetic stirring. It is then diluted with an equal volume of ether and centrifuged. The precipitate is washed three times with an equal volume of ether. The sodium enolate is then covered with about 10 cc. of benzene and a saturated solution of sodium dihydrogen phosphate (pH 4) is added as quickly as possible. The separated aqueous layer is extracted'two more times with ether. The combined organic layers are dried and concentrated in vacuo. The product is recrystallized several times from a mixture of ether and petroleum ether to give 3,3-dimethoxy-22- [methoxa1yl1-2 -spirox-5 ()-ene-21-one, which has the following U IQ Example 3 A solution of 100 mg. of 3,3-dimethoxy-2-[methoxyalyl]--spirox-5(l0)-ene-21-one, dissolved in 6 cc. of pyridine, is cooled to 0 C. Sodium ethoxide (0.26 cc. of l M sodium ethoxide in ethanol) is then added and the resultant solution is flushed with nitrogen for about 2 minutes. With operations conducted behind a shield, perchloryl fluoride is then bubbled into the reaction mixture for 15 minutes at 0 C. and the system is again flushed with nitrogen for about two minutes. The mixture is then poured into water and extracted with ether. The combined ether layers are washed with Water and dried, and the solvent evaporated at room temperature using a rotary evaporator. Final traces of solvent are removed under vacuum.

The residue is dissolved in 4 cc. of absolute ethanol, and 1 cc. of 1 M sodium ethoxide in ethanol is added. The solution is then allowed to stand at room temperature for 2 hours. A precipitate forms. The reaction mixture is carefully acidified, maintaining the temperature-at 0 C., and then poured into water. The mixture is extracted with ether and the ether extract is dried '6 and concentrated in vacuo to give a residue of the crude 3,3-dimethoxy-22-fiuoro-20-spirox-S 10) -ene-2l-one, having the structure indicated below, which is suitable for the next step of the synthesis without further purification.

cHso qg CHaO Example 4 cooled to 0 C. and 2 ml. of 2 N sodium methoxide is then added. The mixture is allowed to stand at room temperature for 2 hours and is then acidified with aqueous sodium dihydrogen phosphate in the cold. Most of the solvent is then removed in vacuo and the residue is extracted With ether. The ether extract is Washed, dried and concentrated in vacuo to give the crude 3,3-dimethoxy-22-bromo-20-spirox-5(10)-ene-21 one having the structure indicated below, which is suitable for the next step of the synthesis without further purification.

OT Iwv Br CHsO CHsO

Example 5 A solution of 3 millimoles of 3,3-dimethoxy-22-methoxalyl-20-spirox-5(10)-ene-21-one, and 3.05 millimoles of pyridine in 25 ml. of dry benzene is cooled to 0 C. To this solution is added slowly with stirring 3 millimoles of chlorine in 25 ml. of benzene. The reacting mixture is allowed to stand for 15 minutes at room temperature and is then poured into water and ether. The organic solvent layer is washed several times with water, dried and then evaporated in vacuo at a temperature less than 35 C. The residue is taken up in 35 ml. of dry methanol cooled to 0 C. and 2 ml. of 2 N sodium methoxide in methanol is then added. The mixture is allowed to stand at room temperature for 2 hours and is then acidified with aqueous sodium dihydrogen phosphate in the cold. Most of the solvent is then removed in vacuo and the residue is extracted with ether. The ether extract is washed, dried and concentrated in vacuo to give the crude 3,3-dimethoxy-22- chloro 20 spirox 5(l0)-ene-21-one having the structure indicated below, which is suitable for the next step of the synthesis without further purification.

OHaO CHaO Example 6 Seventy-three milligrams of 3,3-dimethoxy-22-fluoro- 20-spirox-5(10)-ene-21-one is dissolved in 4 cc. of acetone and 5 mg. of p-toluenesulfonic acid monohydrate in 1 cc. of acetone is added. The solution is warmed on the steam bath for one-half hour. It is then diluted with water and extracted three times with ether. The combined ether extracts are washed With Water, dried and con- 'centrated in vacuo. The residue is chromatographed over acid-Washed alumina and eluated with mixtures of chloroform and ether. Recrystallization from a mixture of methylene chloride and ether affords the substantially pure 22-fluoro-19-nor-20-spirox-4-ene-3,2l-dione, which has the following structure: 7

In accordance with the above procedure, but starting with 3,3-dimethoxy-22-bromo-20-spirox-5 lO)-ene-21-One or 3,3-dimethoxy 22-chloro-20-spirox-S(10)ene-21-One in place of 3,3-dimethoxy-22-fiuoro-20-spirox-5( lO)-ene-21- one, there is obtained the 22 bromo-l9-nor-20-spirox-4- ene-3,2l-dione or 22-chloro-19-nor-20-spirox-4-ene, 3,21- dione, respectively.

Example 7 nor-20-spirox-4,6-diene-3,2l-dione which has the following structure: 1

In accordance with the above procedure, but starting with 22-bromo-19-nor-20-spirox-4-ene-3,21-dione or 22-chloro-19-nor-20-spirox-4-ene-3,l-dione in place of 22- fiuoro-19-nor-20-spirox-4-ene-3,2l-dione, there is obtained the 22-bromo-19-nor-20-spirox4,6-diene-3,21-dione or 22-ch1oro-19-nor-20-spirox-4,6-diene-3,2l-dione,

respectively. r

Example 8 A solution of 80 mg. of 22-fluoro-19-nor-20-spirox- 4,6-diene-3,21-dione in 1.0 m1. of thioacetic acid is heated under reflux on a steam bath for a period of /2 hour. Excess thioacetic acid is evaporated in a stream of nitrogen. Trituration with ether affords crystals which, after two recrystallizations from a mixture of acetone and hexane, gives 7u-acetylthio-22-fluoro-l9-nor- 20-spirox-4-ene-3,21-dione, which has the following structure:

In accordance with the above procedure, but starting with vZZ-bromo-19-nor-2O-spirox-4,6-diene-3,2l-dione or 22-chlorol9-nor-20-spirox-4,6-diene-3,2l-dione in place of 22-fiuoro-l9-nor-2Q-spirox-4,6-diene-3,2l-dione, there is obtained the 7u-acetylthio-22-bromo-19-nor-20-spirox-4- ene-3,21-dione or 7 u-acetylthio-22 chloro 19 nor 20- spirox-4-ene-3,21-dione respectively.

Example 9' A mixture of 1.5 parts by weight of 22-fluoro-19-nor- 20-spirox-4,6-diene-3,21-dione and 1.5 parts by volume of thiopropionic acid is heated on the steam bath for 3 hours. After standing overnight, the reaction mixture is diluted with 25 parts by volume of ether. The crystals which form on cooling are separated and recrystallized from ether and petroleum ether to obtain 7a-propionylthio-22-fluoro-19-nor-20-spirox-4-ene 3,21 dione which has the following structure.

In accordance with the above procedure, but starting with 22-bromo-19-nor-20-spirox-4,6-diene-3,2l-dione or -22-chloro-l9-nor 20-spirox-4,6-diene-3,2l-dione in place of 22-fluoro-19-nor-20-spirox-4,6-diene-3,1 dione, there is obtained the 7a-propionylthio-22-bromo-l9-nor-20 spirox- 4-ene-3,21-dione or the 7a-propionylthio-22-chloro-19- nor-20-spirox-4-ene-3,2l-dione, respectively.

Various changes andmodifications may be made in carrying out the present invention without departing from the spirit. and scope thereof. 'Insofar as these changes and modifications are within the purview of the annexed claims, they are to be considered as part of my invention.

I claim: i

1. 3,3-dimethoxy-20-spirox-5(10)-ene-21-one.

2. The process which comprises reacting 3-methoxy- 17cz- [2'-carboxyethyl] -2,5 (10)-androstadiene-17j3-ol with anhydrous methanol in the presence of an acid catalyst to form 3,3-dimethoxy-20-spirox-5(10) ene-21-one.

3. The process which comprises reacting 3,3 -dimethoxy-ZO-spirox-S(1Q)-ene-21-one with an oxalate ester and a non-aqueous strong base to form 3,3-dimethoxy-22- methdxalyl-ZO-spitox-S 1 0) -21-one.

4. The process which comprises reacting 3,3-dimethoxy- 9 22-methoxaly1-20-spirox-5(10)-ene 21 one sequentially with an alkali metal alkoxide, perchloryl fluoride and then with an alkali metal alkoxide to form 3,3-dimethoxy- 22-fluoro-20-spirox-5 10) -ene-2l -one.

5. The process which comprises reacting 3,3-dimethoxy-22-methoxalyl-20-spirox-5(10)-ene 21 one sequentially with bromine in the presence of an organic base, and then with an alkali metal alkoxide to form 3,3-dimethoxy-22-bromo-20-spirox-5 10)-ene-21-one.

6. The process which comprises reacting 3,3-dimethoxy-22-methoxalyl-20-spirox-S 10) -ene-21-one sequentially with chlorine in the presence of an organic base,

and then with an alkali metal alkoxide to form 3,3-dimethoxy-22-chloro-20-spirox-5 10)-ene-21-one.

References Cited in the file of this patent UNITED STATES PATENTS Dodson et al. Nov. 4, 1958 OTHER REFERENCES Chemical and Engineering News, Sept. 16, 1957, pages 6667. 

1. 3,3-DIMETHOXY-20-SPIROX-5(10)-ENE-21-ONE. 